Terephthalamides and intermediates useful in preparing same



United States Patent 3,193 579 TEREPHTHALAMIDES AND INTERMEDIATE?) USEFUL IN PREPARENG SAME Moses Wolf Goldberg, Upper Montclair, N1, and Sidney Teitel, New York, N.Y., assignors to HofimanmLa Roche line, Nutiey, N.J., a corporation of New Jersey No Drawing. Filed duly 1, 1963, Ser. No. 292,164 6 Claims. (Cl. 266-559) The present invention relates to therapeutic compounds wherein R and R represent a lower alkyl radical such as methyl; Y represents hydrogen, a

group such as 4-(Z-dimethylaminoethoxy)benzyl or lower alkyl; and M is either 0 or 1.

In a preferred embodiment, R and R are both methyl.

In a still more preferred embodiment, R1,3Ild R are methyl, Y is hydrogen and M is 1. The compounds of Formula I may be readily synthe sized by reacting a compound having the formula of wherein R R M and Y have the same meanings as ascribed thereto hereinabove with a terephthaloyl halide such as terephthaloyl chloride or terephthaloyl bromide, preferably the former.

This invention is suitably eiiected in any convenient inert organic solvent such as acetonitrile, acetone, chloroform, toluene or the like. While temperature isnotcritical, the reaction is preferably effected at a temperature from about 20 C. to about 120 C.

In an alternate embodiment for forming compounds of Formula I above, coinpoundscorresponding to Formula II above are treated with a lower alkyl diester of terephthalic acid such as the diethyl ester of terephthalic acid in the presence of an inert organic solvent, e.g. a

group are novel. Such intermediates may be prepared by two alternate courses of procedure. By one route, a substituted benzaldehyde of the formula R1\ Isometric-Geno 7 R2 V is hydrogenated in the presence of ammonia and a palladium-on-calcium carbonate catalyst, in a suitable inert organic solvent, which maybe a lower alkanol such as ethanol. By another route, a substituted benzaldoxime of the formula is hydrogenated in the presence of a palladium-on-carbon catalyst in a suitable inert organic solvent which can be a lower alkanol such as methanol.

The compounds of Formula I above and the said novel intermediates of Formula 11 above wherein Y is a group form acid addition salts with common inorganic or organic acids such as the hydrohalic acids, e.g. hydrochloric, hydrobromic etc., other mineral acids, e.g. nitric, sulfonic, phosphoric etc., arylsulfonic acids, e.g. benzenesulfonic, toluenesulfonic etc., as well as maleic, salicylic,

tartaric, citric, ascorbic, mandelic acids and the like. Such acid addition salts are also within the scope of the present invention.

The formation of said acid addition salts may be eiiected in situ. For example, when forming compounds corregroup can be treated with a sufiicient amount of HCl to form the tetrahydrochloride.

The compounds of this invention are vasodilators of prolonged activity and of especially good compatibility.

They may be used to bring about a lowering of blood pressure and can be used in hypertension.

The compounds of Formula I and their pharmaceutically acceptable acid addition salts can be administered internally, i.e'. parenterally or enterally, by incorporating therapeutic dosages in conventional pharmaceutical liquid or solid vehicles't-o provide elixirs, suspensions, tablets, capsules and the like according to accepted pharmaceutical practice.

The expression lower alkyl, as utilized hereinabove, is intended to c-onnote both straight and branched chained alkyl groups such as methyl, ethyl, ,propyl, isobutyl and the like. a

An especially valuable compoundsuitable for the purposes of the present invent-ion, i.e. as a hypotensive agent, is N,N,-bis[4-(2-dimethylaminoethoxy)benzy1]terephthalamide. g

The following examples are illustrative but not limitative of the present invention. All temperatures are in degree centigrade.

Example 1 To a stirred, refluxing solution of 18.9 g. of 4-(2-dimethylaminoethoxy)aniline in 100 ml. of acetonitri-le, 'there was added, over av 1 hour period, "10.1 g. of ter- 7 and recrystallized from a mixture of water-methanolether to give 4,4'-bis(Z-dimethylaminOethoXy)terephthalanilide dihydrochloride, M.P. 3'14 316 C.

i Example 2 To .a stirred, refluxing solution of 20 .4 g. of 4-(2- dimethylaminoethoxy)benzylamine in '100 ml. of acetonitrile, there was added, over a 1 hour period, 10.1 g. of terephthaloyl chloride dissolved in 100' ml. of acetonitrile. The mixture was stirred and refluxed for 8 hours and then cooled. The crystalline precipitate'formedwas filtered oil and recrystallized from water-eth-anol to give N,N bis[4 (2 dimethylaminoethoxy)benzyl]terephth-alamide 'di-hydrochloride, M.P. 279281 (with decomposition) V Example3 tain di [4 (2 dimethylaminoethoxy)benZyHamine,

An aliquot of the amine, when treated with a solution .of hydrogen chloride in ethanol, gave the crystalline di- [4 (2 dimethylaminoethoxy)benzyl] amine trihydrochloride, melting at 216-263 with decomposition (from methanol-ethanol-ether').. 7

Example 4 To a solution of 9 g. of hydroxylamine hydrochloride and 5.2 g. of sodium hydroxide in 50 ml, ofwater, there was added a solution of 19.3 g. of 4-(2-dimethylaminoethoxy)'benzaldehyde in 70 ml. of ethanol. The res'u-lting solution Was refluxed for /2 hour, cooled, and the crystals that formed were filtered off and dried to give 4-(2-dimethylaminoethoxy) benzaldoxirne, 90-91" 9 g. of IO'percent of palladium-on-ca rbon were added to a solution of 181 g of 4-(2-dimethy1aminoethoxy} V Q 7 a Nomo1120 wmm-rs-p-Qg-n- CHWQ-OoHoH2N '1 r Y o Y n The mixture was hydrogenated at 160? and 4. benzaldoxime in 200 ml. of methanol. The mixture was hydrogenated at 60 and 00 p.s.i until 223 pounds of hydrogen'was taken up. The catalyst was filtered oil, the volatiles distilled off and the residual oil fractionated 5 in high vacuum yielding di-[4-(Z-dimethylaminoethoxy)- benzylJamine,B 213, n 1.5500.

Example 5 To a stirred, refluxing solution of 19.5 g. of di-[4-(2- d-imethylaminoethoxy)benzyl]amine in 50 ml. of acetonitrile,there was added, over 1 hour period, 5.1 g. of te-rephthaloyl chloride dissolved in 50 ml. of acetonitrile. The mixture was stirred and refiuxed for'8 hours and then cooled. The volatiles were distilled oil. The residual solid was dissolved in methanol and to the re sultant solution there was added hydrogen chloride dissolved in ethanol until a pH of 1 was obtained. The volatiles were distilled oil and the residuewas crystal- 'lized from methanol-acetone-ether to yield N,N,N',N'- 20 tetra[4 ('2 dimethylaminoethoxy)benzyl]terephthalamide tet-rahydrochloride monohydrate, melting at 222- 224.

We claim: 1. A comp-oundselected from the group consisting of compounds of the formula wherein R1 and R are each selected from the group consisting of lower alkyl; Y is selected from the group consisting of hydrogen,

1 Nomomoornm h andlower alkyl and Mis an integer of 0 to 1. 4.0 and acid addition salts thereof with pharmaceutically acceptable acids. 2. 4,4',-bis(Z-dimethylaminoethoxy)terephth'alanilide. 3. N,N bis[4} (2 dimethylaminoethoxy)benzyl]- terephthalamide. i 4. N,N,N,N' tetra[4 (2 dimethylaminoethoxy)- benzyflterephthalamide.

5. A compound selected from the group consisting of compounds having the formula of wherein R1 and R are selected from the group consisting 'of'lower alkyl, and acid addition salts thereof with pharm-aceutically ac- .ceptable acids.

6. ,di- [4=(Z-dimethylaminoethoxy)'benzyl] amine.

References Cited by the Examiner 1 UNITED STATES PATENTS V 2,879,293 3/59, Goldberg .et al. 2 60-559 3,047,628. .7/62 Goldberg et a1. 2605.70.7

OTH R REFERENCES 7 Noller: Chemistry ofOrganic Compounds, second ed., a zsz 1957 WALTER A. MODANCE, Primary Examiner. NICHOLAS s, RIZZO, Exa miner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,193,579 July 6, 1965 Moses Wolf Goldberg et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Columns 1 and 2, lines 17 to 21, for that portion of formula (I) reading 1 1 1 -OCH2CH2 read OCH CH N column 1, line 45, for "invention" read reaction column 2, line 1, after "Such" insert novel column 3, line 60, for

"2l6-263" read 261-263 Signed and sealed this 22nd day of February 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA
 5. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA OF 